Regulierung des Energiestoffwechsels und der Lebenslänge durch Indy und durch seine Substrate

• Antragsteller: Professor Dr. Andreas L. Birkenfeld
• Fachliche Zuordnung: Endokrinologie, Diabetologie, Metabolismus ; Gastroenterologie
• Förderung: Förderung von 2011 bis 2019
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 204152872

• Erstellungsjahr: 2020

Zusammenfassung der Projektergebnisse

Before submitting the application, it was known that the reduced expression of the Indy gene in D. melanogaster prolongs lifespan. The underlying mechanism seemed to have similarities to caloric restriction. Within the scope of the application we could prove that the Indy homolog SLC13A5 (mindy) is involved in metabolic regulation in a mammalian model organism. Deletion of the gene in mice led to attenuated nutritionally induced obesity, insulin resistance, and fatty liver in mice. We could demonstrate that these effects were mediated at least in part by the interaction of mindy in the liver and nervous system, and that a temporal effect relationship exists. Whether other organs also contribute to this effect and which areas of the nervous system exactly mediate the effect must be clarified in follow-up studies. The question is of interest for a possible drug development. Mechanistically, we observed a depletion of biochemical energy in the form of ATP in the liver upon deletion of mINDY, with subsequent activation of AMPK, hepatic lipid oxidation and reduced hepatic lipogenesis. According to our data, an additional underlying mechanism may be the regulation of histone acetylation, a fundamental principle in protein function and gene expression. This new effect needs to be further investigated in future studies. Moreover, we were able to show that the proinflammatory cytokine IL-6 leads to an increased expression of mindy in the liver via the transcription actor STAT-3 in mice and humans, and that this mechanism explains an increased expression of mindy in obesity; insulin resistance and NAFLD. The increased expression of mindy in HepG2 and HEK cell lines resulted in an increased synthesis of triglyorides and sterols. This effect could be inhibited by reduced expression of mindy. In conclusion, we postulate that a dietary weight gain and insulin resistance, usually accompanied by elevated IL-6 concentrations, leads to increased expression of the citrate transporter mINDY. According to our data, reduced expression of the transporter would be a valid therapeutic principle in type 2 diabetes, insulin resistance and NAFLD. Based on our data, first mindy inhibitory compounds were developed by industry. https://www.taqesspieqel.de/themen/presseportal/taqesspiegel-magazine-taqesspiegel-gesund/13530724.html https://dresdner-transferbrief.de/ist-das-geheimnis-um-langlebigkeit-bald-gelueftet-und-fuer-den-menschen-nutzbar/ https://www.mdr.de/wissen/prof-andreas-birkenfeld-tu-dresden-100.html https://www.mdr.de/sachsenradio/bild-107636.html

Projektbezogene Publikationen (Auswahl)

• Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell Metab 2011; 14:185-195
  Birkenfeld, Andreas L.; Lee, Hui-Young; Guebre-Egziabher, Fitsum; Alves, Tiago C.; Jurczak, Michael J.; Jornayvaz, Francois R.; Zhang, Dongyang; Hsiao, Jennifer J.; Martin-Montalvo, Alejandro; Fischer-Rosinsky, Antje; Spranger, Joachim; Pfeiffer, Andreas F.; Jordan, Jens; Fromm, Martin F.; König, Jörg; Lieske, Stefanie; Carmean, Christopher M.; Frederick, David W.; Weismann, Dirk; Knauf, Felix; Irusta, Pablo M.; Cabo, Rafael de; Helfand, Stephen L.; Samuel, Varman T.; Shulman, Gerald I.
  
• Hepatic Non Alcoholic Fatty Liver Disease, Hepatic Insulin Resistance and Type 2 Diabetes. Hepatology 2014: 59:713-23
  Birkenfeld AL, Shulman Gl
  
• The Mammalian INDY Homolog is Induced by CREB in a Rat Model of Type 2 Diabetes. Diabetes 2014;63:1048-57
  Neuschäfer-Rube F, Lieske S, Kuna M, Henkel J, Perry RJ, Erion DM, Pesta D, Willmes DM, Tolkachov A, Schupp M, Brachs S, Loeffelholz C, Pathe-Neuschäfer-Rube M, Pfeiffer AFH, Shulman Gl, Püschel GP, Birkenfeld AL
  
• Arylhydrocarbon receptor-dependent mIndy (Slc13a5) induction as possible contributor to benzo[a]pyrene-induced lipid accumulation in hepatocytes. Toxicology. 2015;337:1-9
  Neuschäfer-Rube F, Schraplau A, Schewe B, Lieske S, Krützfeldt JM, Ringel S, Henkel J, Birkenfeld AL, Püschel GP
  
• Knockdown of lndy/CeNac2 extends Caenorhabditis elegans life span by inducing AMPK/aak-2
  Schwarz F, Karadeniz Z, Fischer-Rosinsky A, Willmas DM, Spranger J, Birkenfeld AL
  
• Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5). Aging (Albany NY). 2015;7:1086-93
  Pesta DH, Perry RJ, Guebre-Egziabher F, Zhang D, Jurezak M, Fischer-Rosinsky A, Daniels MA, Willmes DM, Bhanot S, Bomstein SR, Knauf F, Samuel VT, Shulman Gl, Birkenfeld AL
  
• The Role of INDY in Mammalian Metabolism. Comput Struct Biotechnol J. 2013. 6: e201303020
  Willmes DM, Birkenfeld AL
  
• Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice. Mol Metab. 2016;5:1072-1082
  Brachs S, Winkel AF, Tang H, Birkenfeld AL. Brunner B, Jahn-Hofmann K, Margerie D. Ruetten H, Schmoll D, Spranger J
  
• The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism. Hepatology. 2017;66:616-630
  Loeffelholz, Christian von; Lieske, Stefanie; Neuschäfer-Rube, Frank; Willmes, Diana M.; Raschzok, Nathanael; Sauer, Igor M.; König, Jörg; Fromm, Martin F.; Horn, Paul; Chatzigeorgiou, Antonios; Pathe-Neuschäfer-Rube, Andrea; Jordan, Jens; Pfeiffer, Andreas F. H.; Mingrone, Geltrude; Bornstein, Stefan R.; Stroehle, Peter; Harms, Christoph; Wunderlich, F. Thomas; Helfand, Stephen L.; Bernier, Michel; Cabo, Rafael de; Shulman, Gerald I.; Chavakis, Triantafyllos; Püschel, Gerhard P.; Birkenfeld, Andreas L.
  
• The longevity transporter mindy (Slc13a5) as a target for treating hepatic steatosis and insulin resistance. Aging (Albany NY). 2016;8:208-9
  Willmes DM, Hetfand SL, Birkenfeld AL
  
• Analysis of naturally occurring mutations in the human uptake transporter NaCT important for bone and brain development and energy metabolism. Sci Rep. 2018:8:11330
  Selch S, Chafai A, Sticht H, Birkenfeld AL, Fromm MF, König J. A
  
• The longevity gene INDY (I'm Not Dead Yet) in metabolic control: Potential as pharmacological target. Pharmacol Ther 2018:185:1-11
  Willmes DM, Kurzbach A, Henke C, Schumann T, Zahn G, Heifetz A, Jordan J, Helfand SL, Birkenfeld AL
  
• Disruption of the sodium-dependent citrate transporter SLC13A5 in mice causes alterations in brain citrate levels and neuronal network excitability in the hippocampus. Neurobiol Pis. 2G20:143:105018
  Henke, Christine; Töllner, Kathrin; van Dijk, R. Maarten; Miljanovic, Nina; Cordes, Thekla; Twele, Friederike; Bröer, Sonja; Ziesak, Vanessa; Rohde, Marco; Hauck, Stefanie M.; Vogel, Charlotte; Welzel, Lisa; Schumann, Tina; Willmes, Diana M.; Kurzbach, Anica; El-Agroudy, Nermeen N.; Bornstein, Stefan R.; Schneider, Susanne A.; Jordan, Jens; Potschka, Heidrun; Metallo, Christian M.; Köhling, Rüdiger; Birkenfeld, Andreas L.; Löscher, Wolfgang
  
• Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease. Pharmacol Rev. 2020;72:343-379
  Schumann T, König J, Henke C, Willmes DM, Bomstein SR, Jordan J, Fromm MF, Birkenfeld AL